PNNL

Abstract

Background & Aims: The liver transplant model offers the unique opportunity to study longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. Our goal was to identify molecular signatures, and key regulatory proteins, representative of the processes influencing early progression to fibrosis. Methods: We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV+ liver transplant recipients at 6 and 12 months post-transplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by area under the receiver operating characteristic curve (AUC) analysis. Computational modeling approaches were used to further identify key regulatory proteins of liver fibrogenesis. Results: Among 4,324 proteins identified in this study two-hundred-fifty were subsequently determined to exhibit significantly differentially regulated abundances in patients with rapidly progressive fibrosis. Functional analyses of the corresponding proteins suggest that patients with rapidly progressive liver disease exhibit aberrant innate and enhanced inflammatory activities that, together with impaired anti-oxidant defenses, result in elevated oxidative stresses and early hepatic stellate cell activation. Computational modeling approaches further indicate a key regulatory role for glutathione S-transferase kappa 1 (GSTK1), a chaperone of the metabolic regulator adiponectin, as well as several proteins functioning in liver regeneration and stellate cell contractility during early progression to fibrosis. Conclusions: Our results provide new insights into the role of altered innate immune, hepatoprotective and stellate cell activities occurring prior to histological evidence of fibrosis that may also prove useful in prognostic applications for predicting early progression to fibrosis.